WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 526969
Description: PF-06273340 is a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor with an excellent LipE profile (IC50 value: Trk-A = 6 nM; Trk-B = 4 nM; Trk-C = 3 nM). PF-06273340 has low metabolic turnover in HLM and hHep is a good substrate for efflux transporters P-gp (ER = 35.7) and BCRP (ER = 4.0) and has moderate passive permeability (RRCK Papp = 5.4 × 10−6 cm s−1). PF-06273340 is well-tolerated was selected as a candidate for clinical development.
MedKoo Cat#: 526969
Chemical Formula: C23H22ClN7O3
Exact Mass: 479.1473
Molecular Weight: 479.925
Elemental Analysis: C, 57.56; H, 4.62; Cl, 7.39; N, 20.43; O, 10.00
Synonym: PF-06273340; PF 06273340; PF06273340; PF-6273340; PF 6273340; PF6273340.
IUPAC/Chemical Name: N-(5-(2-amino-7-(1-hydroxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide
InChi Key: BPIWZDNVMQQBQX-UHFFFAOYSA-N
InChi Code: InChI=1S/C23H22ClN7O3/c1-23(2,12-32)31-11-18(17-10-28-22(25)30-21(17)31)20(34)13-5-16(9-26-7-13)29-19(33)6-15-4-3-14(24)8-27-15/h3-5,7-11,32H,6,12H2,1-2H3,(H,29,33)(H2,25,28,30)
SMILES Code: NC1=NC=C2C(N(C(C)(C)CO)C=C2C(C3=CN=CC(NC(CC4=CC=C(Cl)C=N4)=O)=C3)=O)=N1
The aqueous solubility of PF-06273340 is 131 μM, much improved over previous analogues, it is highly kinase-selective (Gini score of 0.92) and has no measurable activity at the hERG channel. PF-06273340 was profiled in a series of in vitro safety assays, showing little cytotoxicity in THLE or HepG2 cell lines (IC50 > 42 μM and >300 μM, respectively) and was evaluated for broader pharmacological activity in a panel of receptors, ion channels, and enzymes. In this broad panel, all IC50/Ki values were >10 μM except for COX-1 (IC50 = 2.7 μM) and dopamine transporter assays (Ki = 5.2 μM) and PDEs 4D, 5A, 7B, 8B, and 11 (54−89% inhibition at 10 μM). PF-06273340 was screened in the Invitrogen wide kinase panel of 309 kinases, and all were inhibited by <40% when tested at 1 μM except the following: MUSK (IC50 53 nM), FLT-3 (IC50 395 nM), IRAK1 (IC50 2.5 μM), MKK (90% @ 1 μM), and DDR1 (60% @ 1 μM).
1: Skerratt SE, Andrews MD, Bagal SK, Bilsland J, Brown D, Bungay PJ, Cole S,
Gibson KR, Jones R, Morao I, Nedderman A, Omoto K, Robinson C, Ryckmans T,
Skinner K, Stupple PA, Waldron G. The Discovery of a Potent, Selective and
Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of
Pain. J Med Chem. 2016 Oct 21. [Epub ahead of print] PubMed PMID: 27766865.